Renal Cell Cancer Treatment – Health Professional Version

Incidence and Mortality

Estimated new cases and deaths from renal cell (kidney and renal pelvis) cancer in the United States in 2018:[1]

• New cases: 65,340.
• Deaths: 14,970.

Follow-up and Survivorship

Renal cell cancer, also called renal adenocarcinoma, or hypernephroma, can often be cured if it is diagnosed and treated when still localized to the kidney and to the immediately surrounding tissue. The probability of cure is directly related to the stage or degree of tumor dissemination. Even when regional lymphatics or blood vessels are involved with tumor, a significant number of patients can achieve prolonged survival and probable cure.[2] When distant metastases are present, disease-free survival is poor; however, occasional selected patients will survive after surgical resection of all known tumor. Because a majority of patients are diagnosed when the tumor is still relatively localized and amenable to surgical removal, approximately 73% of all patients with renal cell cancer survive for 5 years.[3] Occasionally, patients with locally advanced or metastatic disease may exhibit indolent courses lasting several years. Late tumor recurrence many years after initial treatment also occasionally occurs.

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

Treatment Modalities

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

Related Summaries

Other PDQ summaries containing information related to renal cell cancer include the following:

• Genetics of Kidney Cancer (Renal Cell Cancer)
• Transitional Cell Cancer of the Renal Pelvis and Ureter Treatment
• Wilms Tumor Treatment

References

1. American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018.
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 November 2, 2017.

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

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]

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.
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
T1	Tumor ≤7 cm in greatest dimension, limited to the kidney.
T1a	Tumor ≤4 cm in greatest dimension, limited to the kidney.
T1b	Tumor >4 cm but not >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 fascia.
T3a	Tumor 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.
T3b	Tumor grossly extends into the vena cava below the diaphragm.
T3c	Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.
T4	Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

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

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.
M0	No distant metastasis.
M1	Distant metastasis.

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.
I	T1	N0	M0
II	T2	N0	M0
III	T1 or T2	N1	M0
	T3	N0 or N1	M0
IV	T4	Any N	M0
	Any T	Any N	M1

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.

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 is defined by the American Joint Committee on Cancer’s TNM classification system:[1]

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:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Kidney. In: 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 is defined by the American Joint Committee on Cancer’s TNM classification system:[1]

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:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Kidney. In: 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 is defined by the American Joint Committee on Cancer’s TNM classification system:[1]

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.[5,3,6]

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:

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Kidney. In: 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 renal cell cancer is defined by the American Joint Committee on Cancer’s TNM classification system:[1]

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

Local Therapy

Tumor embolization, external-beam radiation therapy (EBRT), and nephrectomy can aid in the palliation of symptoms caused by the primary tumor or related ectopic hormone or cytokine production. For patients with metastatic disease, two randomized studies have demonstrated an overall survival (OS) benefit in selected patients who have undergone initial cytoreductive nephrectomy before the administration of interferon-alpha.[2,3] However, the benefit of such surgery has not been evaluated in an era with available antiangiogenic and other targeted therapies.

In the larger study, 246 patients were randomly assigned to either undergo a nephrectomy followed by interferon-alpha or receive interferon-alpha alone.[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 before receiving interferon-alpha had a median OS of 17 months compared with an OS of 7 months in patients who received interferon-alpha alone (hazard ratio [HR], 0.54; 95% CI, 0.31–0.94; P = .03).

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

Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases.[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.

Antiangiogenic and Other Targeted Therapy

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

Anti-vascular endothelial growth factor (VEGF)

Based on research showing that most clear-cell renal cell carcinomas carried a mutation resulting in constitutive production of cytokines stimulating angiogenesis, several agents that targeted VEGF-mediated pathways were developed. Several of these agents have been shown in randomized, controlled trials to significantly delay progression of clear-cell renal cell carcinoma, but none has resulted in a statistically significant increase in OS as conventionally assessed. Many of these trials allowed crossover upon progression and, in some instances, other agents with similar biological activity were available to patients after they withdrew from the clinical trial. These facts may have made it more difficult to detect an OS benefit. For the clinician, this makes it challenging to determine the real benefit of these drugs to the patient. The four FDA-approved anti-VEGF agents include three oral tyrosine kinase inhibitors: pazopanib, sorafenib, and sunitinib; and an anti-VEGF monoclonal antibody, bevacizumab. Axitinib is a newer, highly selective, and more potent inhibitor of VEGF receptors 1, 2, and 3 and has been approved by the FDA for the treatment of advanced renal cell carcinoma after the failure of one previously received systemic therapy.[11]

Sunitinib

Sunitinib and the combination of bevacizumab plus interferon-alpha have each been associated with longer progression-free survival (PFS) than interferon-alpha alone in randomized, controlled trials. Sunitinib is an orally available multikinase inhibitor (VEGFR-1, VEGFR-2, PDGFR, c-Kit). In 750 previously untreated patients, all of whom had clear cell kidney cancer, a phase III trial compared sunitinib with interferon-alpha.[12] 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).[12][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).[13][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.[14] 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.[15,16]

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.[17]

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.[18] Nearly 50% of the patients had previously received cytokine therapy, although the remainder of them were treatment naïve. PFS was significantly prolonged in the pazopanib arm at 9.2 months compared with 4.2 months in the placebo arm. The HR for progression was 0.46 (95% CI, 0.34–0.62; P < .0001), and the median duration of response was longer than 1 year.

Pazopanib was also compared with sunitinib in a randomized, controlled trial (NCT00720941) that enrolled 1,110 patients who had metastatic renal cell carcinoma with a clear-cell component in a 1:1 ratio.[19] The primary endpoint was PFS. The study was powered to assess the noninferiority of pazopanib. Results were reported when there was disease progression in 336 of 557 patients (60%) who received pazopanib and in 323 of 553 patients (58%) who received sunitinib. The median PFS time was 8.4 months for those in the pazopanib arm and 9.5 months for those in the sunitinib arm (HR, 1.05; CI, 0.9–1.22). There was no difference in OS (HR, 0.91; 95% CI, .76–1.08). Although quality of life (QOL) was compared in the study, differences in the scheduled administration of the medications made this comparison difficult to interpret.

A subsequent double-blind, randomized, controlled, cross-over trial compared sunitinib followed by pazopanib with pazopanib followed by sunitinib; the primary endpoint was patient preference for one drug over the other.[20] Patients were treated for 10 weeks with either sunitinib or pazopanib, followed by a 2-week washout period, followed by 10 more weeks of treatment with the other drug. Preference was assessed at the end of the second 10-week treatment period. This study design created possible bias in favor of pazopanib.

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

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

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

Cabozantinib

Cabozantinib is an oral tyrosine kinase inhibitor of the MET, AXL, and VEGF receptors. After a phase I trial showed activity against renal cell carcinoma, a phase III trial randomly assigned 658 patients to receive either cabozantinib (60 mg qd) or everolimus (10 mg qd).[21] Doses were reduced in 60% of the patients receiving cabozantinib compared with 25% of the patients assigned to everolimus, and the incidence of grade 3 or 4 adverse events was 68% with cabozantinib compared with 58% with everolimus. The most common high-grade adverse events were hypertension (15%), diarrhea (11%), and fatigue (9%) with cabozantinib, compared with anemia (16%), fatigue (7%), and hyperglycemia (5%) with everolimus.

Dose reductions of cabozantinib were mainly the result of diarrhea, palmar-plantar erythrodysesthesia syndrome, and fatigue. A planned interim analysis for OS showed a trend toward longer survival for patients who received cabozantinib; however, it did not meet the predetermined boundary for statistical significance for interim analysis, and the published survival curves for the two drugs crossed. At the time of publication, median survival for everolimus had not been reached. PFS was longer for cabozantinib (median, 7.4 months vs. 3.8 months; HR for progression or death, 0.58; 95% CI, 0.45–0.75, P < .001).[21]

Axitinib

Axitinib was shown to prolong PFS when used as second-line systemic therapy. A randomized, controlled trial of 723 patients conducted at 175 sites in 22 countries evaluated axitinib versus sorafenib as treatment for renal cell carcinoma with a clear cell component that had progressed during or after first-line treatment with sunitinib (54%), cytokines (35%), bevacizumab plus interferon (8%), or temsirolimus (3%).[11,22] 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).[22]

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.[11,22]

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.[17]

In an international, multicenter, randomized trial with the primary endpoints of PFS and OS, 769 patients were stratified by the Memorial Sloan Kettering Cancer Center prognostic risk category and by country and were randomly assigned to receive either sorafenib (400 mg bid) or a placebo. Approximately 82% of the patients had received IL-2 previously and/or interferon-alpha in both arms of the study. The median PFS for patients randomly assigned to sorafenib was 167 days compared with 84 days for patients randomly assigned to placebo (P < .001). The estimated HR for the risk of progression with sorafenib compared with a placebo was 0.44 (95% CI, 0.35–0.55). There was no significant difference in OS.[17][Level of evidence: 1iDiii] A subsequent phase II study of 189 patients randomly assigned to either sorafenib or interferon-alpha reported no difference (5.7 months vs. 5.6 months) in PFS, but sorafenib was associated with better QOL than interferon-alpha.[23]

mTOR inhibitors

Temsirolimus

Temsirolimus, an intravenously administered mTOR inhibitor, was shown to result in prolonged OS compared with interferon-alpha in a phase III randomized controlled trial that enrolled intermediate- and poor-risk patients. The trial enrolled patients with a variety of subtypes of renal cell carcinoma and was not restricted to clear cell kidney cancer. The HR for death was 0.73 (95% CI, 0.58–0.92, P = .008), making temsirolimus the only therapy for renal cell carcinoma to clearly show results in longer OS than did interferon-alpha using conventional statistical analysis.[24]

Everolimus

Everolimus is an orally administered mTOR inhibitor that was evaluated in a double-blind, randomized, placebo-controlled phase III trial. The trial enrolled patients with metastatic renal cell carcinoma with a clear cell component that had progressed during or within 6 months of stopping treatment with sunitinib, sorafenib, or both drugs. Median PFS was 4.0 months with everolimus compared with 1.9 months with placebo.[25] No difference in OS was reported.

Immunotherapy

Immune checkpoint inhibitors

Nivolumab

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

After a phase II trial showed promising results and no dose response with nivolumab, which was dosed at 0.3 mg/kg, 2 mg/kg, or 10 mg/kg and administered every 3 weeks,[26] a randomized controlled trial compared nivolumab at a dose of 3 mg/kg every 2 weeks with everolimus at a dose of 10 mg daily.[27] The trial randomly assigned 821 patients with metastatic renal cell carcinoma and a clear cell component who had previously received one or two antiangiogenic regimens. The objective response rate was 25% with nivolumab compared with 5% with everolimus (P < .001). The median duration of treatment was 5.5 months with nivolumab compared with 3.7 months with everolimus, and there was no significant difference in PFS (median PFS, 4.6 months with nivolumab vs. 4.4 months with everolimus). However, OS was significantly longer with nivolumab (median OS, 25.0 months vs. 19.6 months; HR, 0.73; 98.5% CI, 0.57–0.93).[27] In the randomized phase II trial, the median survival was 25.5 months with a dose of 2 mg/kg administered every 3 weeks and 24.7 months with a dose of 10 mg/kg administered every 3 weeks.[26] It is not clear whether the phase III dose of 3 mg/kg every 2 weeks offers any advantage over 2 mg/kg every 3 weeks; however, the latter dose offers substantial cost savings.

Cytokine therapy

Interferon-alpha and interleukin-2 (IL-2)

Cytokine therapy with interferon-alpha or IL-2 has been shown to induce objective responses, and interferon-alpha appears to have a modest impact on survival in selected patients. Interferon-alpha has approximately a 15% objective response rate in appropriately selected individuals.[28] In general, these patients have nonbulky pulmonary or soft tissue metastases with excellent PS ratings of 0 or 1, according to the ECOG rating scale, and the patients show no weight loss. The interferon-alpha doses used in studies reporting good response rates have been in an intermediate range (6–20 million units administered 3 times weekly). A Cochrane analysis of six randomized trials, with a total of 963 patients, indicated an HR for survival of 0.78 (CI, 0.67–0.90) or a weighted average improvement in survival of 2.6 months.[28][Level of evidence: 1iiA]

High-dose IL-2 produces an overall response rate similar to that of interferon-alpha, but approximately 5% of the patients have shown durable complete remissions.[29–34] No randomized, controlled trial of IL-2 has ever shown a longer survival result. High-dose IL-2 is used because it is the only systemic therapy that has been associated with inducing durable complete remissions, albeit in a small fraction (about 5%) of patients who are eligible for this treatment. The optimum dose of IL-2 is unknown. High-dose therapy appears to be associated with higher response rates but with more toxic effects. Low-dose inpatient regimens show activity against renal cell carcinoma with fewer toxic effects, especially hypotension, but have not been shown to be superior to placebo or any alternative regimen in terms of survival or QOL.[35] Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects but, again, with unclear survival or QOL benefit.[36] 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.[37,38]

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:

First-line therapy:

1. Radical nephrectomy (for T4, M0 lesions).
2. Cytoreductive nephrectomy (for any T, M1 lesions).[2,3]
3. Temsirolimus.[24]
4. Sunitinib.[12,13,19,20]
5. Pazopanib.[18–20]
6. Bevacizumab with or without interferon-alpha.[14–16,39]
7. Interferon-alpha.[28,38,40,41]
8. IL-2.[28,34,35]
9. Palliative EBRT.

Second-line therapy:

1. Nivolumab (for patients who have previously been treated with a sunitinib, pazopanib, sorafenib, and/or axitinib).[26]
2. Cabozantinib (for patients who have previously been treated with sunitinib, pazopanib, sorafenib, or axitinib).[21]
3. Axitinib.[22]
4. Everolimus (for patients who have previously been treated with sunitinib and/or sorafenib).[25]
5. Sorafenib.[23,42]
6. Palliative EBRT.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. Nexavar® [label information]. Rockville, Md: Center for Drug Evaluation and Research, FDA, 2007. Available online. Last accessed December 8, 2016.
18. 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]
19. 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]
20. Escudier B, Porta C, Bono P, et al.: Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol 32 (14): 1412-8, 2014. [PUBMED Abstract]
21. Choueiri TK, Escudier B, Powles T, et al.: Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373 (19): 1814-23, 2015. [PUBMED Abstract]
22. 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]
23. 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]
24. 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]
25. 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]
26. Motzer RJ, Rini BI, McDermott DF, et al.: Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 33 (13): 1430-7, 2015. [PUBMED Abstract]
27. Motzer RJ, Escudier B, McDermott DF, et al.: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 373 (19): 1803-13, 2015. [PUBMED Abstract]
28. Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005. [PUBMED Abstract]
29. 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]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. 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]
42. 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]