Local Therapy
Cytokine Therapy
Antiangiogenic Therapy
Chemotherapy
Treatment Options
Current Clinical Trials

Stage IV renal cell cancer is defined by the following stage groupings:

• T4, N0, M0
• T4, N1, M0
• Any T, N2, 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. Because of early reports of success, progestational agents have been administered to patients with metastatic renal cell cancer, but the response rates have been disappointingly low; therefore, no rationale currently exists for their use as anticancer therapy. Progestational agents may, however, offer subjective palliation.

Tumor embolization, external-beam radiation therapy, and nephrectomy can aid in the palliation of symptoms caused by the primary tumor or related ectopic hormone production. Minimal evidence suggests that nephrectomy induces regression of distant metastases; therefore, a nephrectomy performed with the hope that it will be followed by spontaneous regression of metastases is not advised. Spontaneous regressions occasionally occur. A prospective surveillance series of 73 patients with advanced renal cell cancer demonstrated apparent temporary objective regression in five patients (7%) without nephrectomy or any therapy.[1] Selected patients with solitary or a limited number of distant metastases can achieve prolonged survival with nephrectomy and surgical resection of the metastases. Even patients with brain metastases had similar results.[2] 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. Cytoreductive nephrectomy in selected patients who will receive postoperative interferon-α may convey a modest impact on survival. (See the Cytokine therapy section below.)

Cytokine therapy has been shown to induce objective responses and have a modest impact on survival in selected patients. Interferon-alpha has approximately a 15% objective response rate in appropriately selected individuals.[3] In general, these patients have nonbulky pulmonary and/or soft tissue metastases with excellent performance status (PS) ratings of zero or one, according to the Eastern Cooperative Oncology Group 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 a hazard rate (HR) for survival of 0.78 (confidence interval [CI], 0.67–0.90) or a weighted average improvement in survival of 2.6 months.[3][Level of evidence: 1iiA]

Two randomized studies suggest that some patients may benefit from initial cytoreductive nephrectomy prior to the administration of interferon-alpha.[4,5] In the larger study, 246 patients were randomly assigned to either undergo a nephrectomy followed by interferon or receive interferon alone.[4] The median overall survival (OS) was 11.1 months when the primary tumor was removed first (95% CI, 9.2–16.5) compared with 8.1 months (95% CI, 5.4–9.5; P = .05). In a smaller study, 85 patients with identical eligibility criteria and treatment were randomly assigned. Patients who received nephrectomy prior to interferon-alpha had a median OS of 17 months compared with an OS of 7 months in patients receiving interferon-alpha alone (HR = 0.54; 95% CI, 0.31–0.94; P = .03;).[5] Patients were highly selected with characteristics of clear cell carcinoma, small tumors, and a PS of zero to one; they were also considered to be candidates for postoperative immunotherapy.[5][Level of evidence: 1iiA]

Patients who received interleukin-2 (IL-2), with or without lymphokine-activated killer lymphocytes, appeared to have a similar overall response rate to those who received interferon-alpha, but approximately 5% of the appropriately selected patients had durable complete remissions.[6-10] Combinations of IL-2 and interferon have been studied but have not been shown to be better than high-dose IL-2 alone.[11] 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 can retain efficacy with fewer toxic effects, especially hypotension.[12] Outpatient subcutaneous administration has also demonstrated responses with acceptable toxic effects.[13]

Preliminary reports of agents targeting the angiogenesis pathway appear promising. Sorafenib, an orally available multikinase inhibitor (cRAF, bRAF, KIT FLT-3, VEGFT-2, VEGFR-3 and PDGFR-β), is approved for the treatment of patients with advanced renal cell carcinoma.[14,15] In an international, multicenter randomized trial with the primary endpoints of progression-free survival 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 b.i.d.) or a placebo. Approximately 82% of the patients had received prior IL-2 and/or interferon in both arms of the study. The median progression-free survival 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). Results for OS are not yet available.[14][Level of evidence: 1iDiii]

A randomized, double-blind phase II trial compared two doses of bevacizumab, a monoclonal antibody that acts against vascular endothelial growth factor, with placebo in patients with metastatic renal cell cancer.[16] Approximately 93% of patients had received prior IL-2 therapy. Patients receiving high-dose bevacizumab had an increase in median time-to-progression compared with placebo (4.8 vs. 2.5 months; HR = 2.55; P = .001). No significant difference was observed in OS.[16][Level of evidence: 1iDii]

Early reports of other small molecule inhibitors of the angiogenesis pathway, including tyrosine kinase inhibitors of multiple receptors such as sunitinib, also suggest antitumor activity.[17] The exact mechanism is unknown. Sunitinib received accelerated approval by the Food and Drug Administration on the basis of partial response rates and duration of response rates derived from two single-arm, multicenter trials enrolling a total of 169 patients with metastatic renal cell carcinoma progressing after cytokine-based therapy. The first study showed an objective response rate (RR) of 25.5% (95% CI, 17.5–34.9); the second study had an RR of 36.5% (95% CI, 24.7–49.6).[18,19][Level of evidence: 2Div] Data from several prospective, randomized trials with bevacizumab or sunitinib in patients with metastatic renal cancer are not yet available.

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

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.

1. Sorafenib.[14]
2. Sunitinib.[15,17]
3. Bevacizumab.[16]
4. IL-2.[7,8,10,11]
5. Interferon-alpha.[1,20,21]
6. Palliative EBRT.
7. Palliative nephrectomy.[22]
8. Radical nephrectomy (for T4 lesions).[4,5]
9. Surgical excision of metastatic disease with radical nephrectomy (for selected M1 patients).[23]
10. Clinical trials of temsirolimus.[24]
11. Clinical trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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. Oliver RT, Nethersell AB, Bottomley JM: Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol 63 (2): 128-31, 1989.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. Nexavar® [label information]. Rockville, Md: Center for Drug Evaluation and Research, FDA, 2006 Available online. Last accessed July 21, 2008. 
    
    
15. Motzer RJ, Hutson TE, Tomczak P, et al.: Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN-α) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC). [Abstract] J Clin Oncol 24 (Suppl 18): A-LBA3, 2006. 
    
    
16. 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]
    
    
17. Sutent® [label information]. Rockville, Md: Center for Drug Evaluation and Research, FDA, 2006 Available online. Last accessed July 21, 2008. 
    
    
18. Motzer RJ, Michaelson MD, Redman BG, et al.: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24 (1): 16-24, 2006.  [PUBMED Abstract]
    
    
19. Motzer RJ, Rini BI, Michaelson MD: Phase 2 trials of SU11248 show antitumor activity in second-line therapy for patients with metastatic renal cell carcinoma (RCC). [Abstract] J Clin Oncol 23 (Suppl 16): A-4508, 380s, 2005. 
    
    
20. Krown SE: Interferon treatment of renal cell carcinoma. Current status and future prospects. Cancer 59 (3 Suppl): 647-51, 1987.  [PUBMED Abstract]
    
    
21. Muss HB: The role of biological response modifiers in metastatic renal cell carcinoma. Semin Oncol 15 (5 Suppl 5): 30-4, 1988.  [PUBMED Abstract]
    
    
22. deKernion JB, Berry D: The diagnosis and treatment of renal cell carcinoma. Cancer 45 (7 Suppl): 1947-56, 1980.  [PUBMED Abstract]
    
    
23. Neves RJ, Zincke H, Taylor WF: Metastatic renal cell cancer and radical nephrectomy: identification of prognostic factors and patient survival. J Urol 139 (6): 1173-6, 1988.  [PUBMED Abstract]
    
    
24. Hudes G, et al.: A phase III, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-prognosis patients with advanced renal cell carcinoma. [Abstract] J Clin Oncol 24 (Suppl 18): LBA4, 2s, 2006. 
    
    

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