Management of renal cell carcinoma (RCC) has made considerable progress in recent years, and new emerging strategies are being developed. On the basis of the results of two randomised studies in the early 2000s, nephrectomy has now become the standard as cytoreductive surgery before embarking on systemictreatment with cytokines. Interleukin (IL)-2 and interferon were the standard treatment in metastatic RCC (MRCC) until 2006. The efficacy of these two drugs, which have now been used for >20 years in MRCC, is still controversial. On the basis of many studies, these drugs should not be given to patients with a poor prognosis. In patients with good prognostic factors, a cytokine-based regimen should remain the standard as either a high-dose IL-2 or subcutaneous regimen. In patients with intermediate risk, the results of the French Percy Quattro study encourage the use of new targeted therapies as first-line therapy.
Development of targeted therapies in RCC has been necessary largely because the Von Hippel-Lindau (VHL) gene is often mutated in sporadic RCC. VHL protein abnormalities lead to accumulation of hypoxia-inducible factor (HIF)-α and activation of a series of genes, including vascular endothelial growth factor (VEGF), thus inducing angiogenesis. Results from many recent studies with new agents that block the VEGF pathway have been reported and offer new strategic options for patients with MRCC. Sunitinib and sorafenib, two tyrosine kinase inhibitors, improve progression-free survival in RCC compared with standard treatment and have been recently approved. Temsirolimus, a mammalian target of rapamycin inhibitor regulating HIF-α, improves survival in RCC patients with poor risk features. Bevacizumab, a monoclonal antibody against VEGF, has shown very promising efficacy. Overall, treatment of MRCC is currently moving from the cytokine era to the targeted agent era. However, many questions still remain regarding the efficacy of combination treatments and on the best way to achieve complete remission, which is probably the best hope of curing MRCC.
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No sources of funding were used to assist in the preparation of this manuscript. The author has received honoraria from Bayer, Roche, Wyeth and Pfizer.
Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol 2005; 173: 1496–501PubMedCrossRefGoogle Scholar
Lam JS, Leppert JT, Figlin RA, et al. Role of molecular markers in the diagnosis and therapy of renal cell carcinoma. Urology 2005 Nov; 66 (5 Suppl.): 1–9PubMedCrossRefGoogle Scholar
Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon al-fa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001 Dec 6; 345 (23): 1655–9PubMedCrossRefGoogle Scholar
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 2001 Sep 22; 358 (9286): 966–70PubMedCrossRefGoogle Scholar
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 2005; (1): 133–41Google Scholar
Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Eng J Med 1985; 313: 1485–92CrossRefGoogle Scholar
MRC trial. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet 1999 Jan 2; 353 (9146): 14–7CrossRefGoogle Scholar
Pyrhonen S, Salminen E, Ruutu M, et al. Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblas-tine alone in patients with advanced renal cell cancer. J Clin Oncol 1999 Sep; 17 (9): 2859–67PubMedGoogle Scholar
Negrier S, Escudier B, Lasset C, et al. Interleukin-2, interferon or both in 425 patients with metastatic renal cell cancer: results of a multicenter randomized trial. N Engl J Med 1998; 338: 1272–8PubMedCrossRefGoogle Scholar
Escudier B, Chevreau C, Lasset C, et al. Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? J Clin Oncol 1999; 17: 2039–43PubMedGoogle Scholar
Lopez Hänninen E, Kirchner H, Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol 1996; 155: 19–25PubMedCrossRefGoogle Scholar
Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003 Aug 15; 21 (16): 3127–32PubMedCrossRefGoogle Scholar
Upton MP, Parker RA, Youmans A, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 2005 Sep–Oct; 28 (5): 488–95PubMedCrossRefGoogle Scholar
Negrier S, Perol D, Ravaud A, et al. Do cytokines improve survival in patients with metastatic renal cell carcinoma (MRCC) of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial [abstract 4511]. J Clin Oncol 2005; 23: 380sGoogle Scholar
Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Français D’Immunothérapie. Ann Oncol 2002; 13: 1460–8PubMedCrossRefGoogle Scholar
Ohh M, Park CW, Ivan M, et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000; 2 (7): 423–7PubMedCrossRefGoogle Scholar
Lamuraglia M, Escudier B, Chami L, et al. To predict progression-free survival and overall survival in metastatic renal cancer treated with sorafenib: pilot study using dynamic contrast-enhanced Doppler ultrasound. Eur J Cancer 2006; 42 (15): 2472–9PubMedCrossRefGoogle Scholar
Rixe O, Meric J, Bloch J, et al. Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC) [abstract 3003]. J Clin Oncol 2005; 23: 380sGoogle Scholar
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 2003 Jul 31; 349 (5): 427–34PubMedCrossRefGoogle Scholar
Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 2005; 23 (31): 7889–96PubMedCrossRefGoogle Scholar
Bukowski R, Kabbinavar F, Figlin R, et al. Results of a randomised phase II trial of bevacizumab +/- erlotinib in mRCC [abstract 4523]. J Clin Oncol 2006; 24: 18SCrossRefGoogle Scholar
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 2006; 24 (1): 16–24PubMedCrossRefGoogle Scholar
Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006; 295 (21): 2516–24PubMedCrossRefGoogle Scholar
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 meta-static renal cell carcinoma (mRCC) [abstract LBA3]. J Clin Oncol 2006; 24: 18SCrossRefGoogle Scholar
Escudier B, Roigas J, Gillessen S, et al. Continuous daily administration of sunitinib malate (SU11248): aphase II study in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC) [abstract]. Ann Oncol 2006; 17 (9): 4360Google Scholar
Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006 Jun 1; 24 (16): 2505–12PubMedCrossRefGoogle Scholar
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC) [abstract 4510]. J Clin Oncol 2005; 23: 380sGoogle Scholar
Escudier B, Szczylik C, Eisen T, et al. Randomized phase III trial of the multikinase inhibitor sorafenib (BAY43-9006) in patients with advanced renal cell carcinoma (RCC) [abstract 794]. Eur J Cancer 2005; 3: 226Google Scholar
Rini B, Rixe O, Bukowski R, et al. AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC) [abstract 4509]. J Clin Oncol 2005; 23: 380sGoogle Scholar
Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004 Mar 1; 22 (5): 909–18PubMedCrossRefGoogle Scholar
Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC) [abstract LBA4]. J Clin Oncol 2006; 24: 18SCrossRefGoogle Scholar
Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol, 2004; 22 (3): 454–63PubMedCrossRefGoogle Scholar
Rini BI, George DI, Michaelson MD, et al. Efficacy and safety of sunitinib malate in bevacizumab-refractory metastatic renal cell carcinoma [abstract 4522]. J Clin Oncol 2006; 24: 18SCrossRefGoogle Scholar