Questions About Cancer? 1-800-4-CANCER

Renal Cell Cancer Treatment (PDQ®)

Health Professional Version
Last Modified: 02/21/2014

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 2014:[1]

  • New cases: 63,920.
  • Deaths: 13,860.
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 40% of all patients with renal cell cancer survive for 5 years. Occasionally, patients with locally advanced or metastatic disease may exhibit indolent courses lasting several years. Late tumor recurrence many years after initial treatment also occasionally occurs.

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

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 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014. 

  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]

Cellular Classification of Renal Cell Cancer

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

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define renal cell cancer.[5]

Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
T1Tumor ≤7 cm in greatest dimension, limited to the kidney.
T1aTumor ≤4 cm in greatest dimension, limited to the kidney.
T1bTumor >4 cm but not >7 cm in greatest dimension, limited to the kidney.
T2Tumor >7 cm in greatest dimension, limited to the kidney.
T2aTumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.
T2bTumor >10 cm, limited to the kidney.
T3Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.
T3aTumor grossly extends into the renal vein or its segmental (muscle containing) branches, or tumor invades perirenal and/or renal sinus fat but not beyond Gerota fascia.
T3bTumor grossly extends into the vena cava below the diaphragm.
T3cTumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.
T4Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node metastasis.
N1Metastases in regional lymph node(s).

Table 3. Distant Metastasis (M)a
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
M0No distant metastasis.
M1Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groupsa
Stage T N M 
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.
IT1N0M0
IIT2N0M0
IIIT1 or T2N1M0
T3N0 or N1M0
IVT4Any NM0
Any TAny NM1

References
  1. Bassil B, Dosoretz DE, Prout GR Jr: 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: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. 

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

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 fascia, with or without a regional lymph node dissection. Some, but not all, surgeons believe the radical operation yields superior results. In patients who are not candidates for surgery, external-beam radiation therapy (EBRT) or arterial embolization can provide palliation. In patients with bilateral stage I neoplasms (concurrent or subsequent), bilateral partial nephrectomy or unilateral partial nephrectomy with contralateral radical nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.[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]

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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I renal cell cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. 

  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

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 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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II renal cell cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. 

  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

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

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

Treatment information for patients whose disease has the following classification:

  • T3a, N0, M0

Radical resection is the accepted, often curative, therapy for stage III renal cell cancer. The operation includes removal of the kidney, adrenal gland, perirenal fat, and Gerota fascia, with or without a regional lymph node dissection.[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. 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]

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 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 who are not candidates for surgery, arterial embolization can provide palliation. In patients with stage T3b neoplasms who manifest concurrent or subsequent renal cell carcinoma in the contralateral kidney, a partial nephrectomy, when technically feasible, may be a preferred alternative to bilateral nephrectomy with dialysis or transplantation.[3,5,6]

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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III renal cell cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. 

  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

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 prior treatment and site of recurrence, as well as individual patient considerations. Carefully selected patients may benefit from surgical resection of localized metastatic disease, particularly if they have had a prolonged, disease-free interval since their primary therapy.

Local Therapy

Tumor embolization, external-beam radiation therapy (EBRT), and nephrectomy can aid in the palliation of symptoms caused by the primary tumor or related ectopic hormone or cytokine production. For patients with metastatic disease, two randomized studies have demonstrated an overall survival (OS) benefit in selected patients who have undergone initial cytoreductive nephrectomy prior to 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% confidence interval [CI], 9.2–16.5) compared with 8.1 months in the control arm (95% CI, 5.4–9.5; P = .05). In the smaller study, 85 patients with identical eligibility criteria were randomly assigned to treatment as in the larger study.[3] Patients who underwent nephrectomy prior to receiving interferon-alpha had a median OS of 17 months compared with an OS of 7 months in patients who received interferon-alpha alone (hazard ratio [HR], 0.54; 95% CI, 0.31–0.94; P = .03).

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

Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases.[4-9] Even patients with brain metastases had similar results.[10] 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.

Cytokine Therapy

Cytokine therapy with interferon-alpha or interleukin-2 (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.[11] In general, these patients have nonbulky pulmonary and/or soft tissue metastases with excellent PS ratings of zero or one, 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 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.[11][Level of evidence: 1iiA]

High-dose IL-2 produces a similar overall response rate to interferon-alpha, but approximately 5% of patients had durable complete remissions.[12-17] IL-2 has never been shown in a randomized, controlled trial to result in longer survival. 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 have 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 with regard to survival or quality of life.[18] Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or quality of life benefit.[19] 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.[20,21]

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 targeting 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.

Temsirolimus

Temsirolimus, an intravenously administered mTOR inhibitor, was shown to result in prolonged OS compared with interferon-alpha in a phase III randomized controlled trial that enrolled intermediate- and poor-risk patients. The trial enrolled patients with a variety of subtypes of renal cell carcinoma and was not restricted to clear cell kidney cancer. The HR for death was 0.73 (95% CI, 0.58–0.92, P = .008), making temsirolimus the only therapy for renal cell carcinoma to have clearly been shown to result in longer OS than interferon-alpha using conventional statistical analysis.[22]

Everolimus

Everolimus is an orally administered mTOR inhibitor that was evaluated in a double-blind, randomized, placebo-controlled phase III trial. The trial enrolled patients with metastatic renal cell carcinoma with a clear-cell component that had progressed during or within 6 months of stopping treatment with sunitinib or sorafenib, or both drugs. Median progression-free survival (PFS) was 4.0 months with everolimus compared with 1.9 months with placebo.[23] No difference in OS was reported.

Anti-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 vascular endothelial growth factor (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 prior systemic therapy.[24]

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). In 750 previously untreated patients, all of whom had clear-cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha.[25] 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).[25][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).[26][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.[27] 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.[28,29]

Axitinib

Axitinib was shown to prolong progression of disease when used as second-line systemic therapy. A randomized, controlled trial of 723 patients conducted at 175 sites in 22 countries evaluated axitinib versus sorafenib as treatment for renal cell carcinoma with a clear-cell component that had progressed during or after first-line treatment with sunitinib (54%), cytokines (35%), bevacizumab plus interferon (8%), or temsirolimus (3%).[24,30] 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 progression death 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 such that 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.[24,30]

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.[31]

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.[32] Nearly half of the patients had previously received cytokine therapy, although the remainder of them were treatment naïve. PFS was significantly prolonged in the pazopanib arm at 9.2 months compared with 4.2 months in the placebo arm. The HR for progression was 0.46 (95% CI, 0.34–0.62; P < .0001), and the median duration of response was longer than 1 year.

Pazopanib was also compared with sunitinib in a randomized controlled trial (NCT00720941) that enrolled 1,110 patients who had metastatic renal cell carcinoma with a clear-cell component in a 1:1 ratio.[33] 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 557patients (60%) who received pazopanib and 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, .9–1.22). There was no difference in OS (HR, 0.91; 95% CI, .76–1.08). Although quality of life was compared in the study, differences in the scheduled administration of the medications made this comparison difficult to interpret.

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.[31]

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 prior IL-2 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.[31][Level of evidence: 1iDiii] A subsequent phase II study of 189 patients randomly assigned to either sorafenib or interferon-alpha reported no difference (5.7 months vs. 5.6 months) in PFS, but sorafenib was associated with better quality of life than interferon-alpha.[34]

Chemotherapy

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

Treatment Options

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

  1. Radical nephrectomy (for T4, M0 lesions).
  2. Cytoreductive nephrectomy (for any T, M1 lesions).[2,3]
  3. Temsirolimus.[22]
  4. Sunitinib.[25,26]
  5. Pazopanib.[32]
  6. Bevacizumab with or without interferon-alpha.[27-29,35]
  7. Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib).[23]
  8. Sorafenib.[34,36]
  9. Axitinib.[30]
  10. Interferon-alpha.[11,21,37,38]
  11. IL-2.[11,17,18]
  12. Palliative EBRT.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV renal cell cancer and recurrent renal cell cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Kidney. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89. 

  2. Flanigan RC, Salmon SE, Blumenstein BA, et al.: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 345 (23): 1655-9, 2001.  [PUBMED Abstract]

  3. Mickisch GH, Garin A, van Poppel H, et al.: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 358 (9286): 966-70, 2001.  [PUBMED Abstract]

  4. Murthy SC, Kim K, Rice TW, et al.: Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma? Ann Thorac Surg 79 (3): 996-1003, 2005.  [PUBMED Abstract]

  5. van der Poel HG, Roukema JA, Horenblas S, et al.: Metastasectomy in renal cell carcinoma: A multicenter retrospective analysis. Eur Urol 35 (3): 197-203, 1999.  [PUBMED Abstract]

  6. Eggener SE, Yossepowitch O, Kundu S, et al.: Risk score and metastasectomy independently impact prognosis of patients with recurrent renal cell carcinoma. J Urol 180 (3): 873-8; discussion 878, 2008.  [PUBMED Abstract]

  7. Kwak C, Park YH, Jeong CW, et al.: Metastasectomy without systemic therapy in metastatic renal cell carcinoma: comparison with conservative treatment. Urol Int 79 (2): 145-51, 2007.  [PUBMED Abstract]

  8. Russo P, O'Brien MF: Surgical intervention in patients with metastatic renal cancer: metastasectomy and cytoreductive nephrectomy. Urol Clin North Am 35 (4): 679-86; viii, 2008.  [PUBMED Abstract]

  9. Hofmann HS, Neef H, Krohe K, et al.: Prognostic factors and survival after pulmonary resection of metastatic renal cell carcinoma. Eur Urol 48 (1): 77-81; discussion 81-2, 2005.  [PUBMED Abstract]

  10. Wroński M, Arbit E, Russo P, et al.: Surgical resection of brain metastases from renal cell carcinoma in 50 patients. Urology 47 (2): 187-93, 1996.  [PUBMED Abstract]

  11. Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005.  [PUBMED Abstract]

  12. Rosenberg SA, Lotze MT, Muul LM, et al.: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316 (15): 889-97, 1987.  [PUBMED Abstract]

  13. Fisher RI, Coltman CA Jr, Doroshow JH, et al.: Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial. Ann Intern Med 108 (4): 518-23, 1988.  [PUBMED Abstract]

  14. Weiss GR, Margolin KA, Aronson FR, et al.: A randomized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus lymphokine-activated killer cells for advanced renal cell carcinoma. J Clin Oncol 10 (2): 275-81, 1992.  [PUBMED Abstract]

  15. Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30.  [PUBMED Abstract]

  16. 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]

  17. 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]

  18. 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]

  19. 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]

  20. 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]

  21. 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]

  22. Hudes G, Carducci M, Tomczak P, et al.: Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356 (22): 2271-81, 2007.  [PUBMED Abstract]

  23. Motzer RJ, Escudier B, Oudard S, et al.: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372 (9637): 449-56, 2008.  [PUBMED Abstract]

  24. Rini BI, Escudier B, Tomczak P, et al.: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378 (9807): 1931-9, 2011.  [PUBMED Abstract]

  25. Motzer RJ, Hutson TE, Tomczak P, et al.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356 (2): 115-24, 2007.  [PUBMED Abstract]

  26. Motzer RJ, Hutson TE, Tomczak P, et al.: Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 27 (22): 3584-90, 2009.  [PUBMED Abstract]

  27. Yang JC, Haworth L, Sherry RM, et al.: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349 (5): 427-34, 2003.  [PUBMED Abstract]

  28. Rini BI, Halabi S, Rosenberg JE, et al.: Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26 (33): 5422-8, 2008.  [PUBMED Abstract]

  29. Escudier B, Pluzanska A, Koralewski P, et al.: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370 (9605): 2103-11, 2007.  [PUBMED Abstract]

  30. Motzer RJ, Escudier B, Tomczak P, et al.: Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 14 (6): 552-62, 2013.  [PUBMED Abstract]

  31. Nexavar® [label information]. Rockville, Md: Center for Drug Evaluation and Research, FDA, 2007. Available online. Last accessed February 9, 2012. 

  32. Sternberg CN, Davis ID, Mardiak J, et al.: Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28 (6): 1061-8, 2010.  [PUBMED Abstract]

  33. Motzer RJ, Hutson TE, Cella D, et al.: Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369 (8): 722-31, 2013.  [PUBMED Abstract]

  34. Escudier B, Szczylik C, Hutson TE, et al.: Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 27 (8): 1280-9, 2009.  [PUBMED Abstract]

  35. 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]

  36. Escudier B, Eisen T, Stadler WM, et al.: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356 (2): 125-34, 2007.  [PUBMED Abstract]

  37. Pyrhönen S, Salminen E, Ruutu M, et al.: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17 (9): 2859-67, 1999.  [PUBMED Abstract]

  38. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 353 (9146): 14-7, 1999.  [PUBMED Abstract]

Changes to This Summary (02/21/2014)

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.

General Information About Renal Cell Cancer

Updated statistics with estimated new cases and deaths for 2014 (cited American Cancer Society as reference 1).

Stage IV and Recurrent Renal Cell Cancer

Added text to state that pazopanib was also compared with sunitinib in a randomized controlled trial that enrolled 1,110 patients who had metastatic renal cell carcinoma with a renal cell component in a 1:1 ratio (cited Motzer et al. as reference 33). Also added that the primary endpoint was progression-free survival (PFS), and the study was powered to assess the noninferiority of pazopanib. The median PFS time was 8.4 months for those in the pazopanib arm and 9.5 months for those in the sunitinib arm, and there was no difference in overall survival; quality of life was also compared in the study.

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 reviewers for Renal Cell Cancer Treatment are:

  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)
  • Andrew Stephenson, MD (Cleveland Clinic)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. 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:

National Cancer Institute: PDQ® Renal Cell Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/renalcell/HealthProfessional. Accessed <MM/DD/YYYY>.

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 Coping with Cancer: Financial, Insurance, and Legal Information page.

Contact Us

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

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office
9609 Medical Center Dr.
Room 2E532 MSC 9760
Bethesda, MD 20892-9760

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).