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

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 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, some patients will survive after surgical resection of all known tumor. Because most patients are diagnosed when the tumor is still relatively localized and amenable to surgical removal, approximately 75% 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 regression occurs 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.

References
  1. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed June 21, 2024.
  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 February 8, 2024.

Cellular Classification of Renal Cell Cancer

Approximately 85% of renal cell cancers are adenocarcinomas, mostly of proximal tubular origin. Most of the remainder are transitional cell carcinomas of the renal pelvis. For more information, see Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment. 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 I a
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.Stage 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.
–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 II a
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.Stage 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.
–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 III a
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.Stage 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, the right and left adrenal glands, and the vena cava.
–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 IV a
StageTNMDefinitionIllustration
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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).Stage 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.
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. Springer; 2017, pp 739–48.

Treatment Option Overview

Current treatment cures more than 50% of patients with stage I renal cell cancer, but patients with stage IV disease have very poor outcomes. All patients with newly diagnosed renal cell cancer are candidates for clinical trials, when possible.

Treatment of Stage I Renal Cell Cancer

Treatment Options for Stage I Renal Cell Cancer

Treatment options for stage I renal cell cancer include the following:

  1. Partial nephrectomy (selected patients).[1,2]
  2. Radical nephrectomy.[2]
  3. Simple nephrectomy.[2]
  4. Cryotherapy.
  5. Thermal ablation.
  6. Stereotactic ablative body radiation therapy (SABR or SBRT) (also referred to as stereotactic radiosurgery).
  7. External-beam radiation therapy (EBRT) (palliative).[2]
  8. Arterial embolization (palliative).[2,3]
  9. Clinical trials.

Surgical resection is the accepted, often curative, therapy for patients with stage I renal cell cancer. In appropriately selected patients, partial nephrectomy has oncologic outcomes that are comparable with radical nephrectomy. Partial nephrectomy also has the benefits of preserving greater renal function and, according to some studies, reduced mortality.[4-7] When the entire kidney is removed, resection may be simple or radical. Radical resection includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. Radical nephrectomy is preferred if the tumor extends into the inferior vena cava.

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.[1] 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.[8]

In patients who are not candidates for resection, there are several curative alternatives, including cryoablation, thermal ablation, and SABR (or SBRT).[9-13]

In patients who are not candidates for the treatments above, EBRT or arterial embolization can provide palliation.

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. 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]
  2. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]
  3. 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]
  4. Kim SP, Thompson RH, Boorjian SA, et al.: Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol 188 (1): 51-7, 2012. [PUBMED Abstract]
  5. Larcher A, Capitanio U, Terrone C, et al.: Elective Nephron Sparing Surgery Decreases Other Cause Mortality Relative to Radical Nephrectomy Only in Specific Subgroups of Patients with Renal Cell Carcinoma. J Urol 196 (4): 1008-13, 2016. [PUBMED Abstract]
  6. Wang Z, Wang G, Xia Q, et al.: Partial nephrectomy vs. radical nephrectomy for renal tumors: A meta-analysis of renal function and cardiovascular outcomes. Urol Oncol 34 (12): 533.e11-533.e19, 2016. [PUBMED Abstract]
  7. Patel HD, Pierorazio PM, Johnson MH, et al.: Renal Functional Outcomes after Surgery, Ablation, and Active Surveillance of Localized Renal Tumors: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 12 (7): 1057-1069, 2017. [PUBMED Abstract]
  8. Thrasher JB, Robertson JE, Paulson DF: Expanding indications for conservative renal surgery in renal cell carcinoma. Urology 43 (2): 160-8, 1994. [PUBMED Abstract]
  9. El Dib R, Touma NJ, Kapoor A: Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies. BJU Int 110 (4): 510-6, 2012. [PUBMED Abstract]
  10. Gkentzis A, Oades G: Thermal ablative therapies for treatment of localised renal cell carcinoma: a systematic review of the literature. Scott Med J 61 (4): 185-191, 2016. [PUBMED Abstract]
  11. Zargar H, Atwell TD, Cadeddu JA, et al.: Cryoablation for Small Renal Masses: Selection Criteria, Complications, and Functional and Oncologic Results. Eur Urol 69 (1): 116-28, 2016. [PUBMED Abstract]
  12. Salagierski M, Wojciechowska A, Zając K, et al.: The Role of Ablation and Minimally Invasive Techniques in the Management of Small Renal Masses. Eur Urol Oncol 1 (5): 395-402, 2018. [PUBMED Abstract]
  13. Siva S, Ali M, Correa RJM, et al.: 5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney). Lancet Oncol 23 (12): 1508-1516, 2022. [PUBMED Abstract]

Treatment of Stage II Renal Cell Cancer

Treatment Options for Stage II Renal Cell Cancer

Treatment options for stage II renal cell cancer include the following:

  1. Partial nephrectomy (selected patients).[1]
  2. Radical nephrectomy.[1]
  3. Radical nephrectomy followed by adjuvant pembrolizumab (high-risk patients).[2]
  4. Nephrectomy before or after external-beam radiation therapy (EBRT) (selected patients).[1]
  5. EBRT (palliative).[1]
  6. Arterial embolization (palliative).
  7. Clinical trials.

Surgical resection is the accepted, often curative, therapy for patients with stage II renal cell cancer. In appropriately selected patients, partial nephrectomy has oncologic outcomes that are comparable with radical nephrectomy. Partial nephrectomy also has the benefits of preserving greater renal function and, according to some studies, reduced mortality.[3-6] When the entire kidney is removed, resection may be simple or radical. Radical resection includes removal of the kidney, adrenal gland, perirenal fat, and Gerota's fascia, with or without a regional lymph node dissection. Radical nephrectomy is preferred if the tumor extends into the inferior vena cava. Lymphadenectomy is commonly used, but its effectiveness has not been definitively proven.

Postoperative systemic therapy with the anti-programmed death-1 (PD-1) antibody pembrolizumab has been shown to prolong disease-free survival (DFS), but not overall survival (OS), in patients with high-risk pT2 tumors.

In patients who are not candidates for surgery, arterial embolization can provide palliation.

Adjuvant pembrolizumab

Pembrolizumab is an immune checkpoint inhibitor and a monoclonal antibody targeting the PD-1 protein.

Evidence (adjuvant pembrolizumab):

  1. A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell carcinoma at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was DFS.[2]

Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[8] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[9,10] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[8,11]

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. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]
  2. Choueiri TK, Tomczak P, Park SH, et al.: Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 385 (8): 683-694, 2021. [PUBMED Abstract]
  3. Kim SP, Thompson RH, Boorjian SA, et al.: Comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta-analysis. J Urol 188 (1): 51-7, 2012. [PUBMED Abstract]
  4. Larcher A, Capitanio U, Terrone C, et al.: Elective Nephron Sparing Surgery Decreases Other Cause Mortality Relative to Radical Nephrectomy Only in Specific Subgroups of Patients with Renal Cell Carcinoma. J Urol 196 (4): 1008-13, 2016. [PUBMED Abstract]
  5. Wang Z, Wang G, Xia Q, et al.: Partial nephrectomy vs. radical nephrectomy for renal tumors: A meta-analysis of renal function and cardiovascular outcomes. Urol Oncol 34 (12): 533.e11-533.e19, 2016. [PUBMED Abstract]
  6. Patel HD, Pierorazio PM, Johnson MH, et al.: Renal Functional Outcomes after Surgery, Ablation, and Active Surveillance of Localized Renal Tumors: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 12 (7): 1057-1069, 2017. [PUBMED Abstract]
  7. Powles T, Tomczak P, Park SH, et al.: Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23 (9): 1133-1144, 2022. [PUBMED Abstract]
  8. Tannock IF, Goldstein DA, Ofer J, et al.: Evaluating Trials of Adjuvant Therapy: Is There Benefit for People With Resected Renal Cancer? J Clin Oncol 41 (15): 2713-2717, 2023. [PUBMED Abstract]
  9. Pal SK, Uzzo R, Karam JA, et al.: Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 400 (10358): 1103-1116, 2022. [PUBMED Abstract]
  10. Motzer RJ, Russo P, Grünwald V, et al.: Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet 401 (10379): 821-832, 2023. [PUBMED Abstract]
  11. Merino M, Kasamon Y, Theoret M, et al.: Irreconcilable Differences: The Divorce Between Response Rates, Progression-Free Survival, and Overall Survival. J Clin Oncol 41 (15): 2706-2712, 2023. [PUBMED Abstract]

Treatment of Stage III Renal Cell Cancer

Treatment Options for Stage III Renal Cell Cancer

Treatment options for stage III renal cell cancer include the following:

  1. Radical nephrectomy.[1]
  2. Preoperative embolization and radical nephrectomy.[2,3]
  3. Radical nephrectomy followed by adjuvant systemic therapy with pembrolizumab or sunitinib.[4,5]
  4. External-beam radiation therapy (EBRT) (palliative).[2]
  5. Tumor embolization (palliative).[3]
  6. Palliative nephrectomy.
  7. Preoperative or postoperative EBRT and radical nephrectomy.[2]
  8. Clinical trials involving adjuvant interferon-alpha.

Adjuvant systemic therapy

Surgical resection is the standard treatment for patients with clinical stage III renal cell cancer. Several different studies have investigated whether adjuvant (postoperative) systemic therapy improves outcomes. None of these trials have demonstrated any impact on overall survival (OS). However, two agents are associated with longer relapse-free survival.

Adjuvant pembrolizumab

Pembrolizumab is an immune checkpoint inhibitor and a monoclonal antibody targeting the programmed death-1 (PD-1) protein.

Evidence (adjuvant pembrolizumab):

  1. A double-blind, randomized, placebo-controlled trial (KEYNOTE-564 [NCT03142334]) studied the impact of 1 year of pembrolizumab after nephrectomy. The study enrolled 994 patients with clear cell renal cell cancer at high risk of recurrence after nephrectomy. Eligibility included patients with stage II disease with nuclear grade 4 or sarcomatoid differentiation, stage III disease or higher, regional lymph node metastases, or stage M1 status with no evidence of disease after resection. Patients were randomly assigned to receive up to 12 months of pembrolizumab (200 mg) or placebo administered intravenously every 21 days. The primary end point was disease-free survival (DFS).[4]

Questions have been raised about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial.[7] An uneven number of patients dropped out in the early follow-up period, which led to a lack of information about recurrence in the control group for the censored patients. Only 36% of the 166 patients in the control group received immunotherapy at relapse, despite conclusive evidence for an OS advantage when immunotherapy is given to patients with metastatic disease. Two other trials using atezolizumab or nivolumab plus ipilimumab failed to show a significant difference in DFS or OS.[8,9] These issues suggest that the U.S. Food and Drug Administration approval of pembrolizumab in the adjuvant setting, and the guidelines released by the National Comprehensive Cancer Network and the European Society for Medical Oncology may have been premature. Further follow-up for more mature DFS and especially OS results is needed.[7,10]

Adjuvant sunitinib

Sunitinib is an oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor pathway.

  1. A double-blind, placebo-controlled, randomized trial (NCT00375674) studied the impact of sunitinib after nephrectomy in patients with locoregional, high-risk, clear cell renal cell cancer (stage T3 or higher and/or regional lymph node metastases). The study randomly assigned 615 patients to receive either 1 year of sunitinib (50 mg) or placebo once daily for the first 4 weeks of a repeating 6-week cycle (i.e., a 4-week-on, 2-week-off schedule).[5]

Treatment options for patients with T3a, N0, M0 disease

Radical resection is the accepted, often curative therapy for patients with 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.[11] Lymphadenectomy is commonly used, but its effectiveness has not been definitively proven. EBRT has been given before or after nephrectomy, without conclusive evidence that it improves survival compared with the results of surgery alone. However, it may benefit 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.[12]

In patients who are not candidates for surgery, arterial embolization can provide palliation.

Treatment options for patients with T3b, N0, M0 disease

Radical resection is the accepted, often curative therapy for patients with 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.[11] Lymphadenectomy is commonly used, 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.[1] EBRT has been given before or after nephrectomy, without conclusive evidence that it improves survival compared with the results of surgery alone. However, it may benefit selected patients with more extensive tumors.

In patients with stage T3b neoplasms who manifest concurrent or subsequent renal cell cancer in the contralateral kidney, a partial nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.[12-14]

In patients who are not candidates for surgery, arterial embolization can provide palliation.

Treatment options for patients with T1, N1, M0; T2, N1, M0; or T3, N1, M0 disease

This stage of renal cell cancer is curable with surgery in a small minority of patients. 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 used preoperatively to reduce blood loss at nephrectomy or for palliation in patients with inoperable disease.

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. 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]
  2. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980. [PUBMED Abstract]
  3. 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]
  4. Choueiri TK, Tomczak P, Park SH, et al.: Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 385 (8): 683-694, 2021. [PUBMED Abstract]
  5. Ravaud A, Motzer RJ, Pandha HS, et al.: Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 375 (23): 2246-2254, 2016. [PUBMED Abstract]
  6. Powles T, Tomczak P, Park SH, et al.: Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 23 (9): 1133-1144, 2022. [PUBMED Abstract]
  7. Tannock IF, Goldstein DA, Ofer J, et al.: Evaluating Trials of Adjuvant Therapy: Is There Benefit for People With Resected Renal Cancer? J Clin Oncol 41 (15): 2713-2717, 2023. [PUBMED Abstract]
  8. Pal SK, Uzzo R, Karam JA, et al.: Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet 400 (10358): 1103-1116, 2022. [PUBMED Abstract]
  9. Motzer RJ, Russo P, Grünwald V, et al.: Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial. Lancet 401 (10379): 821-832, 2023. [PUBMED Abstract]
  10. Merino M, Kasamon Y, Theoret M, et al.: Irreconcilable Differences: The Divorce Between Response Rates, Progression-Free Survival, and Overall Survival. J Clin Oncol 41 (15): 2706-2712, 2023. [PUBMED Abstract]
  11. Phillips E, Messing EM: Role of lymphadenectomy in the treatment of renal cell carcinoma. Urology 41 (1): 9-15, 1993. [PUBMED Abstract]
  12. 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]
  13. deKernion JB: Management of renal adenocarcinoma. In: deKernion JB, Paulson DF, eds.: Genitourinary Cancer Management. Lea and Febiger, 1987, pp 187-217.
  14. 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]

Treatment of Stage IV and Recurrent Renal Cell Cancer

Treatment Options for First-Line Therapy for Stage IV Renal Cell Cancer

Treatment options for first-line therapy for stage IV renal cell cancer include the following:

  1. Ipilimumab plus nivolumab (for patients with intermediate or poor-risk disease).[1]
  2. Pembrolizumab plus axitinib.[2]
  3. Pembrolizumab plus lenvatinib.[3]
  4. Nivolumab plus cabozantinib.[4]
  5. Radical nephrectomy (for T4, M0 lesions).
  6. Cytoreductive nephrectomy (for any T, M1 lesions in patients with good-risk disease).[5-8]
  7. Cabozantinib (for patients with intermediate- or poor-risk disease).[9,10]
  8. Avelumab plus axitinib.[11]
  9. Sunitinib.[12-15]
  10. Pazopanib.[14-16]
  11. Sorafenib.[17]
  12. Temsirolimus.[18]
  13. Bevacizumab with or without interferon-alpha.[19-22]
  14. Interferon-alpha.[23-26]
  15. Interleukin-2 (IL-2).[23,27,28]
  16. Palliative external-beam radiation therapy (EBRT).

Treatment Options for Second-Line Therapy for Stage IV Renal Cell Cancer

Treatment options for second-line therapy for stage IV renal cell cancer include the following:

  1. Nivolumab (for patients previously treated with sunitinib, pazopanib, sorafenib, and/or axitinib).[29]
  2. Lenvatinib plus everolimus (for patients previously treated with sunitinib, pazopanib, cabozantinib, axitinib, or sorafenib).[30]
  3. Cabozantinib (for patients previously treated with sunitinib, pazopanib, sorafenib, or axitinib).[31]
  4. Axitinib.[32]
  5. Everolimus (for patients previously treated with sunitinib and/or sorafenib).[33]
  6. Sorafenib.[34]
  7. Palliative EBRT.

Treatment Options for Third- and Fourth-Line Therapy for Stage IV Renal Cell Cancer

Treatment options for third- and fourth-line therapy for stage IV renal cell cancer include the following:

  1. Tivozanib.[35,36]
  2. Any of the agents listed for first- or second-line therapy.

The prognosis is poor for any patients with renal cell cancer that is progressing, recurring, or relapsing after treatment, regardless of cancer cell type or stage of disease. Almost all patients with stage IV renal cell cancer have incurable disease. The use 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.

Immunotherapy

Immune checkpoint inhibitors

Immune checkpoint inhibitors are drugs that block certain proteins that inhibit the immune system's response to cancer. 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 death-1 (PD-1), programmed cell death-ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).

Ipilimumab plus nivolumab

In a randomized controlled trial, the combination of ipilimumab and nivolumab prolonged overall survival (OS) when compared with sunitinib as first-line systemic therapy for patients with advanced-stage renal cell carcinoma.[1] 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 ipilimumab and nivolumab 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 end points were OS, progression-free survival (PFS), and objective response rate in patients with intermediate- or poor-risk disease. Of note, because there were three primary end points, the overall alpha level of 0.05 was divided among the three end points. 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, 847 of whom had intermediate- or poor-risk disease.
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 protein. 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.

  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.[29]

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 IL-2

Cytokine therapy with interferon-alpha or IL-2 has been shown to induce objective responses. 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.[23] In general, these patients have nonbulky pulmonary or soft tissue metastases with excellent performance status ratings of 0 or 1, according to the Eastern Cooperative Oncology Group (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.[23][Level of evidence A1]

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.[27,38-42] 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 quality of life (QOL).[28] Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or QOL benefit.[43] Combinations of IL-2 and interferon-alpha have been studied, but outcomes have not been better than with high-dose or low-dose IL-2 alone.[24,44]

Combined Immune Checkpoint Inhibitors and Antiangiogenic Targeted Therapies

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

Pembrolizumab plus axitinib

Evidence (pembrolizumab plus axitinib):

  1. An open-label, phase III, randomized controlled trial (NCT02853331) compared sunitinib with the combination of pembrolizumab and axitinib. The study enrolled 861 patients who had received no previous systemic therapy for metastatic disease.[2]

Pembrolizumab plus lenvatinib

Evidence (pembrolizumab plus lenvatinib):

  1. An open-label, phase III, randomized controlled trial (NCT02811861) compared sunitinib with either lenvatinib plus pembrolizumab or lenvatinib plus everolimus. The study enrolled 1,609 patients who had received no previous systemic therapy for metastatic disease.[3]

Nivolumab plus cabozantinib

Evidence (nivolumab plus cabozantinib):

  1. An open-label, phase III, randomized controlled trial (NCT03141177) compared sunitinib with nivolumab plus cabozantinib. The study enrolled 651 patients who had received no previous systemic therapy for metastatic disease.[46]

Avelumab plus axitinib

Evidence (avelumab plus axitinib):

  1. An open-label, phase III, randomized trial (NCT02684006) compared the combination of avelumab and axitinib with sunitinib monotherapy. The study included 560 patients with previously untreated stage IV PD-L1–positive renal cell carcinoma (the entire study population was 886 patients, including those who were PD-L1 negative).[11] This trial specified two primary end points: PFS and OS among patients with PD-L1-positive tumors. PFS among the entire study population was a secondary end point.

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, 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 OS benefit in selected patients who underwent initial cytoreductive nephrectomy before the administration of interferon-alpha.[5,6] However, 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. The limited data available from retrospective nonrandomized studies suggest a benefit in good-risk patients in the current era of targeted therapies.

The CARMENA trial (NCT00930033) evaluated the effectiveness of cytoreductive nephrectomy before targeted therapy. The study reported no benefit for patients who underwent cytoreductive nephrectomy before receiving treatment with sunitinib, an oral antiangiogenic tyrosine kinase inhibitor.[7] 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 rating of 0 or 1, according to the ECOG rating scale; these patients were also considered candidates for postoperative immunotherapy.

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 performance status rating of 0 to 1 and good- or intermediate-risk disease.[8] 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.

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; therefore it was underpowered.[7] In this study, 43% of the patients had poor-risk disease and 57% had intermediate-risk disease.

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.[5,6]

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.[47-52] Even patients with brain metastases had similar results.[53] 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.

Antiangiogenic and Other Targeted Therapy

A growing understanding of the biology of cancer in general, and renal cell cancer 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) and multitargeted tyrosine kinase inhibitors (TKIs)

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 circumstances 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 TKIs: 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. The FDA approved axitinib for the treatment of advanced renal cell carcinoma after the failure of one previously received systemic therapy.[54]

Cabozantinib

Cabozantinib is an oral TKI 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.

  1. The METEOR trial (NCT01865747) randomly assigned 658 patients who had previously been treated with a VEGF TKI to receive either cabozantinib (60 mg qd) or everolimus (10 mg qd).[31,55] Doses were reduced in 60% of the patients receiving cabozantinib, compared with 25% of the patients assigned to everolimus.
  1. Adverse events were seen in more than 95% of the patients.
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).

  1. In 750 previously untreated patients, all of whom had clear cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha.[12]

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.[19] 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.[20,21]

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.

  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.[16] Nearly 50% of the patients had previously received cytokine therapy, although the remainder of them were treatment naïve.
Sorafenib

Sorafenib is an orally available multikinase inhibitor (CRAF, BRAF, KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFRB) and has also been approved for the treatment of patients with advanced renal cell carcinoma.[57]

  1. In an international, multicenter, randomized trial, 769 patients were stratified by the Memorial Sloan Kettering Cancer Center prognostic risk category and by country. Patients 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 primary end points were PFS and OS.
Axitinib

Axitinib has been shown to prolong PFS when used as second-line systemic therapy.

  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. Patients had disease with a clear cell component that had progressed during or after first-line treatment with sunitinib (54%), cytokines (35%), bevacizumab plus interferon-alpha (8%), or temsirolimus (3%).[32,54] The primary end point 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.

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.[32,54]

Tivozanib

Tivozanib is a TKI that is selective for the VEGF receptor. A phase III randomized controlled trial compared tivozanib with sorafenib for first-line treatment of patients with metastatic renal cell cancer. The study reported that tivozanib was associated with a longer median PFS, but OS favored sorafenib.[35] A subsequent phase III randomized controlled trial compared the two drugs in patients who had at least two prior systemic treatments, including at least one prior VEGF inhibitor. This second trial reported a longer median PFS for patients treated with tivozanib and no difference in OS.[36] In the United States, the FDA has approved tivozanib for patients who have had two or more prior systemic therapies.

  1. In an open-label, phase III, randomized controlled trial, tivozanib was compared with sorafenib as initial targeted therapy. The study included 517 patients with metastatic renal cell cancer with a clear cell component who had received zero to one prior systemic therapy. Prior treatment with VEGF-targeted therapy and mTOR inhibitors was not permitted. The primary end point was PFS.[35]

Mammalian target of rapamycin (mTOR) inhibitors

Temsirolimus

Temsirolimus is an intravenously administered mTOR inhibitor.

  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.
Everolimus

Everolimus is an orally administered mTOR inhibitor.

  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.

Combined Therapy With Multitargeted TKIs and mTOR Inhibitors

Lenvatinib plus everolimus

Lenvatinib is a multitargeted tyrosine kinase inhibitor with activity against VEGFR-1, VEGFR-2, and VEGFR-3, with inhibitory activity against fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3, and FGFR4), PDGFRA, RET, and KIT.

Evidence (lenvatinib plus everolimus):

  1. The combination of lenvatinib plus everolimus was compared with each medication as a single agent in a randomized, controlled phase II study of 153 subjects with advanced-stage renal cell carcinoma who had received previous antiangiogenic therapy.[30] The primary end point was PFS.

Chemotherapy

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

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.

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Latest Updates to This Summary (03/01/2024)

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.

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 1).

Revised the list of treatment options for stage I renal cell cancer.

Added text to state that, in appropriately selected patients, partial nephrectomy has oncologic outcomes that are comparable with radical nephrectomy. Partial nephrectomy also has the benefits of preserving greater renal function and, according to some studies, reduced mortality (cited Kim et al., Larcher et al., Wang et al., and Patel et al. as references 4–7, respectively). Also added text to state that radical nephrectomy is preferred if the tumor extends into the inferior vena cava.

Added text to state that, for patients who are not candidates for resection, there are several curative alternatives, including cryoablation, thermal ablation and stereotactic ablative body radiation therapy (cited EI Dib et al., Gkentzis et al., Zargar et al., Salagierski et al., and Siva et al. as references 9–13, respectively).

Added text to state that, in appropriately selected patients, partial nephrectomy has oncologic outcomes that are comparable with radical nephrectomy. Partial nephrectomy also has the benefits of preserving greater renal function and, according to some studies, reduced mortality (cited Kim et al., Larcher et al., Wang et al., and Patel et al. as references 3–6, respectively). Also added text to state that radical nephrectomy is preferred if the tumor extends into the inferior vena cava.

Revised text about the results of the KEYNOTE-564 trial to state that a subsequent report with a median follow-up of 30 months showed a 75.2% disease-free survival (DFS) rate for patients who received pembrolizumab, compared with 65.5% for patients who received placebo (cited Powles et al. as reference 7). Also revised text about adverse events. Added text about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial (cited Tannock et al., Pal et al., Motzer, Russo et al., and Merino et al. as references 8–11, respectively).

Revised text about the results of the KEYNOTE-564 trial to state that a subsequent report with a median follow-up of 30 months showed a 75.2% disease-free survival (DFS) rate for patients who received pembrolizumab, compared with 65.5% for patients who received placebo (cited Powles et al. as reference 6). Also revised text about adverse events. Added text about confounding issues that may have resulted in the significant improvement in DFS in the KEYNOTE-564 trial (cited Tannock et al., Pal et al., Motzer, Russo et al., and Merino et al. as references 7–10, respectively).

Added text about health-related quality of life results from an open-label, phase III, randomized controlled trial that compared sunitinib with either lenvatinib plus pembrolizumab or lenvatinib plus everolimus (cited Motzer, Porta et al. as reference 45 and level of evidence B2).

Revised text about the results of an open-label, phase III, randomized controlled trial that compared sunitinib with nivolumab plus cabozantinib (cited Motzer, Powles et al. as reference 46 and level of evidence A1).

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® Cancer Information for Health Professionals 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 in the care of their 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:

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 reviewers for Renal Cell Cancer Treatment are:

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.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Renal Cell Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated . Available at: https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq. Accessed . [PMID: 26389256]

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